Paclitaxel formulation

Abstract

A pharmaceutical formulation is provided for delivering paclitaxel in vivo comprising: water and micelles comprising paclitaxel and a pharmaceutically-acceptable, water-miscible solubilizer forming the micelles, the solubilizer selected from the group consisting of solubilizers having the general structureswherein R1 is a hydrophobic C3-C50 alkane, alkene or alkyne and R2 is a hydrophilic moiety. The solubilizer is selected such that it does not have a pKa less than about 6.

What is claimed is:  
     
       1. A water-miscible non-aqueous composition for delivering paclitaxel in vivo comprising: 
       paclitaxel;  
       a water-miscible non-aqueous solvent;  
       ascorbic acid; and  
       a pharmaceutically-acceptable, water-miscible solubilizer selected from the group consisting of solubilizers having the general structures  
       
         
           R1COOR2, R1CONR2, and R1COR2,  
         
       
       wherein R1 is a derivative of d-α-tocopherol and R2 is a hydrophilic moiety. 
     
     
       2. The composition according to  claim 1  wherein, upon the addition of water, the solubilizer forms micelles within which the paclitaxel is solubilized in the aqueous solution. 
     
     
       3. The composition according to  claim 1  wherein the solubilizer is esterified d-α-tocopherol. 
     
     
       4. The composition according to  claim 1  wherein the solubilizer is d-α-tocopherol polyethylene glycol succinate (TPGS). 
     
     
       5. The composition according to  claim 1  wherein the solvent is water-miscible alcohol. 
     
     
       6. The composition according to  claim 1  wherein the solvent is selected from the group consisting of ethanol, propylene glycol, benzyl alcohol, polyethylene glycol (PEG). 
     
     
       7. The composition according to  claim 1  wherein the solvent is water-miscible amide. 
     
     
       8. The composition according to  claim 1  wherein the solvent is selected from the group consisting of 2-pyrrolidone, N-methyl-pyrrolidone and N,N-dimethyl acetamide. 
     
     
       9. The composition according to  claim 1  wherein the concentration of solubilzer in the composition is between about 40%w/w and 90%w/w. 
     
     
       10. The composition according to  claim 1  wherein the concentration of solubilzer in the composition is between about 45%w/w and 75%w/w. 
     
     
       11. The composition according to  claim 1  wherein the concentration of solubilzer in the composition is between about 50%w/w and 60%w/w. 
     
     
       12. The composition according to  claim 1  wherein the weight ratio of the solubilizer to the solvent is between about 90:10 and 40:60. 
     
     
       13. The composition according to  claim 1  wherein the weight ratio of the solubilizer to the solvent is between about 70:30 and 45:55. 
     
     
       14. The composition according to  claim 1  wherein the weight ratio of the solubilizer to the solvent is about 50:50. 
     
     
       15. The composition according to  claim 1 , wherein the amount of ascorbic acid is between about 0.1-1%w/w. 
     
     
       16. The composition according to  claim 1 , wherein the amount of ascorbic acid is between about 0.4-0.6%w/w. 
     
     
       17. The composition according to  claim 1 , wherein ascorbic acid is at a concentration sufficient to result in a pH between about 3 and 6. 
     
     
       18. The composition according to  claim 1 , wherein ascorbic acid is at a concentration sufficient to result in a pH between about 4 and 5. 
     
     
       19. A water-miscible non-aqueous composition made by the act comprising: 
       i) dissolving paclitaxel in a water-miscible non-aqueous solvent;  
       ii) dissolving a pharmaceutically-acceptable, water-miscible solubilizer in said solvent at a weight ratio between about 90:10 and 40:60, the solubilizer being selected from the group consisting of solubilizers having the general structures  
       
         
           R 1 COOR 2 , R 1 CONR 2 , and R 1 COR 2 ,  
         
       
       wherein R1 is a derivative of d-α-tocopherol and R2 is a hydrophilic moiety; 
       iii) mixing the paclitaxel solution produced in step i) and the solution containing the solubilizer in step ii); and  
       iv) adding ascorbic acid at a concentration of about 0.1%-1%w/w based on the total weight of the composition to the mixture produced in step iii).  
     
     
       20. A pharmaceutical formulation made by the acts comprising: 
       providing a water-miscible non-aqueous composition comprising paclitaxel, a water-miscible non-aqueous solvent and a pharmaceutically-acceptable, water-miscible solubilizer selected from the group consisting of solubilizers having the general structures  
       
         
           R 1 COOR 2 , R 1 CONR 2 , and R 1 COR 2 ,  
         
       
       wherein R 1  is a derivative of d-α-tocopherol and R 2  is a hydrophilic moiety; and 
       combining the composition with an aqueous solution, wherein, upon addition of the aqueous solution, the solubilizer forms micelles within which the paclitaxel is solubilized in the aqueous solution.  
     
     
       21. A method for administering paclitaxel to a host in need thereof comprising: 
       providing a pharmaceutical formulation comprising: water, ascorbic acid and micelles comprising paclitaxel and a pharmaceutically-acceptable, water-miscible solubilizer forming the micelles, the solubilizer selected from the group consisting of solubilizers having the general structures  
       
         
           R1COOR2, R1CONR2, and R1COR2,  
         
       
       wherein R1 is a hydrophobic C3-C50 alkane, alkene or alkyne and R2 is a hydrophilic moiety; and 
       administering the pharmaceutical formulation in a therapeutically effective amount to a host in need thereof.  
     
     
       22. The composition of  claim 19 , wherein the solvent is ethanol. 
     
     
       23. The composition of  claim 19 , wherein the solubilizer is d-α-tocopherol polyethylene glycol succinate (TPGS). 
     
     
       24. The composition of  claim 19 , wherein the weight ratio of the solubilizer to the solvent is between 70:30. 
     
     
       25. The composition of  claim 19 , wherein the concentration of ascorbic acid is about 0.4%-0.6%w/w based on the total weight of the composition. 
     
     
       26. The method of  claim 21 , wherein the pharmaceutical formulation further comprises an excipient selected from the group consisting of α-, β-, γ-cyclodextrin, and amorphous cyclodextrin.